tbuckley/cabot-search huggingface dataset:
Recent Advancements in Electroporation Technologies: From Bench to Clinic
Authors: Sabrina N. Campelo, Po-Hsun Huang, Cullen R. Buie, Rafael V. Davalos
Journal: Annual Review of Biomedical Engineering (2023)

Over the past decade, the increased adoption of electroporation-based technologies has led to an expansion of clinical research initiatives. Electroporation has been utilized in molecular biology for mammalian and bacterial transfection; for food sanitation; and in therapeutic settings to increase drug uptake, for gene therapy, and to eliminate cancerous tissues. We begin this article by discussing the biophysics required for understanding the concepts behind the cell permeation phenomenon that is electroporation. We then review nano- and microscale single-cell electroporation technologies before scaling up to emerging in vivo applications.
Predictive Models for Health Deterioration: Understanding Disease Pathways for Personalized Medicine
Authors: Bjoern M. Eskofier, Jochen Klucken
Journal: Annual Review of Biomedical Engineering (2023)

Artificial intelligence (AI) and machine learning (ML) methods are currently widely employed in medicine and healthcare. A PubMed search returns more than 100,000 articles on these topics published between 2018 and 2022 alone. Notwithstanding several recent reviews in various subfields of AI and ML in medicine, we have yet to see a comprehensive review around the methods’ use in longitudinal analysis and prediction of an individual patient's health status within a personalized disease pathway. This review seeks to fill that gap. After an overview of the AI and ML methods employed in this field and of specific medical applications of models of this type, the review discusses the strengths and limitations of current studies and looks ahead to future strands of research in this field. We aim to enable interested readers to gain a detailed impression of the research currently available and accordingly plan future work around predictive models for deterioration in health status.
Acculturation and Psychopathology
Authors: Gail M. Ferguson, José M. Causadias, Tori S. Simenec
Journal: Annual Review of Clinical Psychology (2023)

Acculturation and psychopathology are linked in integrated, interactional, intersectional, and dynamic ways that span different types of intercultural contact, levels of analysis, timescales, and contexts. A developmental psychopathology approach can be useful to explain why, how, and what about psychological acculturation results in later adaptation or maladaptation for acculturating youth and adults. This review applies a conceptual model of acculturation and developmental psychopathology to a widely used framework of acculturation variables producing an Integrated Process Framework of Acculturation Variables (IP-FAV). This new comprehensive framework depicts major predisposing acculturation conditions (why) as well as acculturation orientations and processes (how) that result in adaptation and maladaptation across the life span (what). The IP-FAV is unique in that it integrates both proximal and remote acculturation variables and explicates key acculturation processes to inform research, practice, and policy.
Piezoelectric Bioactive Glasses Composite Promotes Angiogenesis by the Synergistic Effect of Wireless Electrical Stimulation and Active Ions
Authors: Changhao Li, Siyu Zhang, Yichen Yao, Yanlan Wang, Cairong Xiao, Bo Yang, Jingyan Huang, Weichang Li, Chengyun Ning, Jinxia Zhai, Peng Yu, Yan Wang
Journal: Advanced Healthcare Materials (2023)

Abstract Insufficient angiogenesis frequently occurs after the implantation of orthopedic materials, which greatly increases the risk of bone defect reconstruction failure. Therefore, the development of bone implant with improved angiogenic properties is of great importance. Mimicking the extracellular matrix clues provides a more direct and effective strategy to modulate angiogenesis. Herein, inspired by the bioelectrical characteristics of the bone microenvironment, a piezoelectric bioactive glasses composite (P‐KNN/BG) based on the incorporation of polarized potassium sodium niobate is constructed, which could effectively promote angiogenesis. It is found that P‐KNN/BG has exceptional wireless electrical stimulation performance and sustained active ions release. In vitro cell experiments reveal that P‐KNN/BG enhances endothelial cell adhesion, migration, and differentiation via activating the eNOS/NO signaling pathway, which might be contributed to cell membrane hyperpolarization induced by wireless electrical stimulation increase the influx of active ions into the cells. In vivo chick chorioallantoic membrane experiment demonstrates that P‐KNN/BG shows excellent pro‐angiogenic capacity and biocompatibility. This work broadens the current understanding of bioactive materials with bionic electrical properties, which brings new insights into the clinical treatment of bone defect repair.
Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial
Authors: Tim Flaadt, Ruth L. Ladenstein, Martin Ebinger, Holger N. Lode, Helga Björk Arnardóttir, Ulrike Poetschger, Wolfgang Schwinger, Roland Meisel, Friedhelm R. Schuster, Michaela Döring, Peter F. Ambros, Manon Queudeville, Jörg Fuchs, Steven W. Warmann, Jürgen Schäfer, Christian Seitz, Patrick Schlegel, Ines B. Brecht, Ursula Holzer, Tobias Feuchtinger, Thorsten Simon, Johannes H. Schulte, Angelika Eggert, Heiko-Manuel Teltschik, Toni Illhardt, Rupert Handgretinger, Peter Lang
Journal: Journal of Clinical Oncology (2023)

PURPOSE Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB. METHODS Patients age 1-21 years underwent T-/B-cell–depleted haplo-SCT followed by DB and scIL2. The primary end point ‘success of treatment’ encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD. RESULTS Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1−6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred. CONCLUSION DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.
Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond
Authors: Simone Caielli, Zurong Wan, Virginia Pascual
Journal: Annual Review of Immunology (2023)

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
Discovering chronic pain treatments: better animal models might help us get there
Authors: Norman E. Taylor, Luiz Ferrari
Journal: Journal of Clinical Investigation (2023)

Only three classes of pain medications have made it into clinical use in the past 60 years despite intensive efforts and the need for nonaddictive pain treatments. One reason for the failure involves the use of animal models that lack mechanistic similarity to human pain conditions, with endpoint measurements that may not reflect the human pain experience. In this issue of the JCI, Ding, Fischer, and co-authors developed the foramen lacerum impingement of trigeminal nerve root (FLIT) model of human trigeminal neuralgia that has improved face, construct, and predictive validities over those of current models. They used the FLIT model to investigate the role that abnormal, hypersynchronous cortical activity contributed to a neuropathic pain state. Unrestrained, synchronous glutamatergic activity in the primary somatosensory cortex upper lip and jaw (S1ULp-S1J) region of the somatosensory cortex drove pain phenotypes. The model establishes a powerful tool to continue investigating the interaction between the peripheral and central nervous systems that leads to chronic pain.
Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors
Authors: Katherine R. Tuttle
Journal: Journal of Clinical Investigation (2023)

The sodium-glucose cotransporter-2 (SGLT2) is expressed on the luminal side of proximal tubule epithelial cells in the kidney. While pharmacological inhibition of SGLT2 provides kidney protection in diabetic kidney disease (DKD), the molecular mechanisms remain unclear. In this issue of the JCI, Schaub et al. report on the changes in single-cell transcriptional profiles of young participants with type 2 diabetes who received SGLT2 inhibitors. Treatment with SGLT2 inhibitors restored metabolic perturbations in proximal tubular cells and reduced expression of the inflammatory signaling molecule mTORC1. Notably, changes in transcripts and mTORC1 were also found in the kidney of a diabetes mouse model treated with an SGLT2 inhibitor, supporting use of this model for further studies. These findings reveal cellular mechanisms of SGLT2 inhibitors and are important for advancing therapeutic targets in the treatment of DKD.
IL-1β suppression of VE-cadherin﻿﻿ transcription underlies sepsis-induced inflammatory lung injury
Authors: Shiqin Xiong, Zhigang Hong, Long Shuang Huang, Yoshikazu Tsukasaki, Saroj Nepal, Anke Di, Ming Zhong, Wei Wu, Zhiming Ye, Xiaopei Gao, Gadiparthi N. Rao, Dolly Mehta, Jalees Rehman, Asrar B. Malik
Journal: Journal of Clinical Investigation (2023)

In the original version of Figure 4D, the representative lung histology sections of control and LPS-exposed animals, specifically the Rolipram (5 mg/kg)/PBS, Rolipram (5 mg/kg)/LPS, Rolipram (10 mg/kg)/PBS, and Rolipram (10 mg/kg)/LPS samples, inadvertently showed overlapping images from the same slide due to an error in figure assembly.The correct figure is shown below.The authors regret the error.
TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis
Authors: Chengzi Huang, Simin Zhao, Yajuan Yang, Ting Guo, Hanni Ke, Xin Mi, Yingying Qin, Zi-Jiang Chen, Shidou Zhao
Journal: Journal of Clinical Investigation (2023)

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.
CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer
Authors: Caishang Zheng, Yanjun Wei, Peng Zhang, Longyong Xu, Zhenzhen Zhang, Kangyu Lin, Jiakai Hou, Xiangdong Lv, Yao Ding, Yulun Chiu, Antrix Jain, Nelufa Islam, Anna Malovannaya, Yun Wu, Feng Ding, Han Xu, Ming Sun, Xi Chen, Yiwen Chen
Journal: Journal of Clinical Investigation (2023)

Emerging evidence suggests that cryptic translation within long noncoding RNAs (lncRNAs) may produce novel proteins with important developmental/physiological functions. However, the role of this cryptic translation in complex diseases (e.g., cancer) remains elusive. Here, we applied an integrative strategy combining ribosome profiling and CRISPR/Cas9 screening with large-scale analysis of molecular/clinical data for breast cancer (BC) and identified estrogen receptor α–positive (ER+) BC dependency on the cryptic ORFs encoded by lncRNA genes that were upregulated in luminal tumors. We confirmed the in vivo tumor-promoting function of an unannotated protein, GATA3-interacting cryptic protein (GT3-INCP) encoded by LINC00992, the expression of which was associated with poor prognosis in luminal tumors. GTE-INCP was upregulated by estrogen/ER and regulated estrogen-dependent cell growth. Mechanistically, GT3-INCP interacted with GATA3, a master transcription factor key to mammary gland development/BC cell proliferation, and coregulated a gene expression program that involved many BC susceptibility/risk genes and impacted estrogen response/cell proliferation. GT3-INCP/GATA3 bound to common cis regulatory elements and upregulated the expression of the tumor-promoting and estrogen-regulated BC susceptibility/risk genes MYB and PDZK1. Our study indicates that cryptic lncRNA-encoded proteins can be an important integrated component of the master transcriptional regulatory network driving aberrant transcription in cancer, and suggests that the "hidden" lncRNA-encoded proteome might be a new space for therapeutic target discovery.
Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects
Authors: Saket Jain, Jonathan W. Rick, Rushikesh S. Joshi, Angad Beniwal, Jordan Spatz, Sabraj Gill, Alexander Chih-Chieh Chang, Nikita Choudhary, Alan T. Nguyen, Sweta Sudhir, Eric J. Chalif, Jia-Shu Chen, Ankush Chandra, Alexander F. Haddad, Harsh Wadhwa, Sumedh S. Shah, Serah Choi, Josie L. Hayes, Lin Wang, Garima Yagnik, Joseph F. Costello, Aaron Diaz, Dieter Henrik Heiland, Manish K. Aghi
Journal: Journal of Clinical Investigation (2023)

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-β as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.
Chronic pain and premature mortality in men and women, using data from UK Biobank
Authors: Gary J. Macfarlane, Marcus Beasley, Gareth T. Jones
Journal: Journal of Clinical Investigation (2023)

To the Editor: Muralidharan et al. (1) demonstrated that 4 months after nerve injury, male (but not female) mice demonstrated telomere length reduction and p53-mediated cellular senescence in the spinal cord, which was associated with pain chronicity and a decreased lifespan.They analyzed data from UK Biobank and concluded that their sex-specific observations in mice of a decreased lifespan were replicated in humans.The basis of this conclusion was a finding that among men in UK Biobank, a larger number of pain sites reported at recruitment associated with an earlier age at death (slope -0.19, P = 0.00011), while among women, the relationship between pain sites and death was much weaker and not statistically significant (slope -0.039, P = 0.51).We believe that the method of analysis was inappropriate, and the authors have come to an incorrect conclusion on this specific point.If one wishes to examine the risk associated with pain status and death, the optimal approach is to follow participants prospectively and to quantify the risk of death in relevant groups.Muralidharan instead only considered participants who had already died and ignored data from people who were yet to die, despite the fact that they also contribute informative data to the question being answered.We have previously published UK Biobank data examining the relationship between chronic widespread pain […]
The World Health Organization’s pandemic treaty
Authors: Alexandra L Phelan
Journal: BMJ (2023)

The covid-19 pandemic showed that gross inequities in population morbidity, mortality, and access to medicines persist between nations, reflecting the colonial histories and current political status of international governance.These patterns of inequity emerge directly from colonialism's racism, violence, resource extraction, and exploitation.It is therefore welcome that "equity" underpins the World Health Organization's call to action to its member states, as they negotiate a new international instrument to advance collective action for pandemic prevention, preparedness, and response-the pandemic treaty. 1 The treaty aims to create legally binding obligations between countries and to establish new global mechanisms for pandemics under the auspices of WHO.On 1 February 2023, WHO released a Zero Draft of the Pandemic Treaty for its member states' consideration at the meetings of the intergovernmental negotiating body in February and April 2023.
The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function
Authors: William Grey, Samantha Atkinson, Beatrice Rix, Pedro Casado, Linda Ariza-McNaughton, Cathy Hawley, Miriam L. Sopoena, Katherine S. Bridge, David Kent, Pedro R. Cutillas, Dominique Bonnet
Journal: HemaSphere (2023)

Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation—broadly termed protein homeostasis or “proteostasis”—in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 −/− and Cks2 −/− mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function.